The Role of Tranexamic Acid in the Management of an Acutely Hemorrhaging Patient

Abstract

Background: Acute hemorrhage, both traumatic and nontraumatic, leads to significant morbidity and mortality, both in the United States and globally. Traditional treatment of acute hemorrhage is focused on hemostasis and blood product replacement. Tranexamic acid is an antifibrinolytic agent that may reduce acute hemorrhage through inhibition of plasminogen. Newer research suggests that coagulopathy, specifically fibrinolysis, may contribute significantly to the pathology of acute hemorrhage. Methods: We searched the PubMed database for relevant articles from 2000 to 2018 for the terms “tranexamic acid,” “TXA,” “antifibrinolytic,” “hyperfibrinolysis,” and “coagulopathy.” Our search was limited to studies published in the English language. Results: A total of 53 studies were included in this review. These articles suggest a potential role for tranexamic acid in the management of acute intracranial hemorrhage, epistaxis, hematuria, postpartum hemorrhage, gastrointestinal hemorrhage, and trauma-related hemorrhage. A theoretical risk of thrombotic events following tranexamic acid use exists, though large clinical trials suggest this risk remains exceedingly small. Conclusions: Recent studies suggest a mortality benefit with tranexamic acid following acute hemorrhage. First responders such as emergency medical technicians and emergency department clinicians should consider tranexamic acid as an adjunct therapy in the management of acute, severe traumatic and nontraumatic hemorrhage.

Introduction

Acute hemorrhage represents a significant cause of morbidity and mortality. In the United States, an estimated 60 000 people die annually as a result of acute hemorrhage. ¹ Global estimates of death from blood loss are 1.9 million per year, most of which result from traumatic injury. Uncontrolled hemorrhage causes nearly one-third of all trauma-related deaths. ²

Severe blood loss leads to widespread tissue ischemia as oxygen supply decreases. ³ A cascading inflammatory response follows, causing further tissue injury and cellular death. ⁴ Simultaneous derangements in coagulation can produce both accelerated hemorrhage and microcirculatory thrombosis. Hemorrhage-associated hypoperfusion of the brain and myocardium can cause death within minutes. ⁵

Current approaches to acute hemorrhage vary by location and severity of injury, availability of therapeutic options, and local expertise in acute and trauma care. Broadly, hemorrhage management is centered on obtaining rapid hemostasis, restoring tissue perfusion, treating coagulopathy, and mitigating the inflammatory response. ² Despite continuous improvement in the understanding and management of acute hemorrhage, there remains no consensus on emergent treatment of patients with massive hemorrhage.

Recent literature has directed significant interest toward the role of fibrinolysis in propagating hemorrhagic shock and the effect of tranexamic acid (TXA) on attenuating fibrinolysis.

Discovered in 1962, TXA has remained a therapeutic option in the management of operative and gynecologic bleeding for 5 decades^6,7; however, recent research focusing on the role of fibrinolysis in hemorrhage has drawn new attention to TXA in diverse clinical settings.^8,9

In this narrative review, we discuss the current evidence on TXA use in acute hemorrhage in general trauma, traumatic brain injury (TBI), epistaxis, hematuria, postpartum hemorrhage, and gastrointestinal (GI) bleeding in the out-of-hospital and emergency department (ED) settings.

Methods

We searched the PubMed database for English-language studies, including randomized clinical trials (RCTs), meta-analyses, systematic reviews, practice guidelines, case studies, case series, and observational studies, using the following terms: “tranexamic acid,” “TXA,” “antifibrinolytic,” “hyperfibrinolysis,” and “coagulopathy.” The sample size, study setting, and design were recorded in each of the studies. A review was also conducted on the reference lists of included articles to detect additional studies for inclusion. Abstracts, unpublished data, and duplicate articles were excluded. Studies published prior to 2000 were removed from consideration in this review, and emphasis was given to the selection of RCTs and meta-analyses in adult populations, with higher priority being given to RCTs with larger patient enrollment. After review, a total of 53 peer-reviewed studies were included.

Mechanism of Action

Tranexamic acid, a synthetic lysine analogue, inhibits plasminogen conversion to plasmin by preventing its interaction with tissue plasminogen activator (tPA). Plasmin plays a central role in fibrinolysis and clot breakdown. In the setting of acute blood loss, physiologic plasmin-mediated fibrinolysis can reduce hemorrhage-associated microvascular thrombosis that might otherwise result in further tissue injury. Pathologic increases in fibrinolysis, or hyperfibrinolysis, can occur following acute hemorrhage, resulting in consumptive coagulopathy and an acceleration of hemorrhagic blood loss. Tranexamic acid can reduce fibrinolysis by decreasing plasmin concentration.^10-15 Plasmin is also a known activator of inflammatory cells, cytokines, and immune mediators; tranexamic acid may mitigate post-injury inflammatory responses through plasmin inhibition. ¹⁶

Results

Application of TXA in Trauma

Trauma is the leading cause of death among individuals aged 45 years and younger in the United States, and is the fourth leading cause of death among Americans of all ages. ¹⁷ Exsanguination is the principle cause of death in trauma, though central nervous system injury and multiorgan failure contribute to trauma mortality.^18,19 During severe traumatic hemorrhage, hypotension and hypoperfusion can precipitate hyperfibrinolysis, wherein fibrin is rapidly depleted. ²⁰ As clot integrity diminishes, coagulopathy ensues, accelerating bleeding and further increasing mortality.^20,21 Although arrest of fibrinolysis appears to be the principal mechanism through which TXA decreases mortality, evidence for additional anti-inflammatory mechanisms exists. ²² Following acute trauma and hemorrhage, plasmin-mediated inflammation may contribute to multiorgan failure. Tranexamic acid may further mitigate trauma-associated mortality by blunting plasmin-mediated inflammation. ¹⁶ Multiple studies have described TXA use in patients following traumatic injury, administered as 1 g intravenously, with or without a subsequent 1-g infusion for ongoing or recurrent bleeding.

Efficacy in civilian trauma

In the largest study of TXA to date, the CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage) investigators enrolled 20 211 patients from 40 countries in an RCT following acute traumatic injury with, or at risk of, significant hemorrhage. ¹⁹ The authors reported an absolute reduction in in-hospital mortality of 2.4% with intravenous TXA (1 g loading dose over 10 minutes, followed by 1 g over 8 hours) compared with placebo when given within 3 hours of injury (P = .0035). A nonsignificant trend toward benefit with TXA was further noted for the composite endpoint (within 4 weeks after injury) of death or dependence (defined as dead or requiring intermittent or continuous medical attention). The study noted that the mortality benefit was limited to those receiving treatment within 3 hours of injury.

In a subsequent prospective cohort study by Cole et al, TXA administration (1 g administered in the ED within 3 hours of injury, followed by a 1-g infusion at the discretion of the trauma team leader when hemorrhage was detected or suspected) was associated with reduced all-cause mortality (P = .03) and multiorgan failure (P = .01) in a subset of severely injured trauma patients with evidence of shock. The authors showed that this mortality benefit did not extend to less severely injured patients. ²² Boutonnet et al ²³ similarly found a survival benefit among 684 severely injured patients (defined as hemodynamic instability requiring red blood cell transfusion) in a retrospective cohort study of TXA use within 3 hours of severe traumatic injury (P < .001). Khan et al reported an increase in 6-hour survival with TXA (87% for TXA vs 66% for no-TXA) following severe traumatic injury in 118 patients with laboratory evidence of hyperfibrinolysis as determined by thromboelastography (TEG). Despite this improvement in 6-hour mortality, no measurable survival benefit was seen at 30 days. The authors reported this as a consequence of the study being underpowered to detect this difference ²⁴ (Table 1). A recent study by Moore et al ²⁵ showed in a prospective cohort of 630 patients that TXA could enhance clot strength in patients with depletion of fibrinolysis inhibitors and hyperfibrinolysis in severe traumatic injury.

Table 1.

Selected Studies Analyzing the Efficacy of TXA Administration in Civilian Trauma.

Authors	Design	No. of patients	Methods	Dosing	Result
Shakur et al 19	Double-blinded RCT	20 211	For patients with or at risk of significant bleeding (systolic blood pressure < 90 mm Hg or heart rate > 110 beats per minute, or both), TXA was given within 8 hours of injury.	TXA 1-g IV bolus and subsequent 1-g IV infusion over 8 hours	TXA was associated with reduced all-cause mortality (14.5% for the TXA group vs 16.0% for the placebo group) and risk of death from bleeding if given in <3 hours (4.9% for TXA vs 5.7% for placebo). Effect is greater if given in <1 hour.
Cole et al 22	Prospective cohort	160	Severely injured adult patients (defined as injury severity score > 15)	TXA 1-g IV bolus and subsequent 1-g IV infusion over 8 hours	TXA was associated with reduced multiorgan failure (P = .03) and all-cause mortality (P = .01) in patients experiencing shock.
Boutonnet et al 23	Retrospective cohort	1476	Inhospital mortality was compared between patients at 6 level 1 trauma centers receiving TXA or not receiving it.	Dosage regimens not recorded	TXA was associated with reduced mortality only in patients with significant hemorrhage (qualified by hemodynamic instability) requiring pRBC transfusion (HR, 0.3; 95% CI, 0.3-0.6 compared with HR, 1.2; 95% CI, 0.8-2.6) (P < .001).
Khan et al 24	Retrospective cohort	118	Mortality at several time points and total time to achieve hemostasis was compared between 31 patients who received TXA and 62 who did not.	Dosage regimens not recorded	TXA was associated with improved 6-hour survival (13% for TXA vs 34% for no-TXA) in patients with hyperfibrinolysis (P = .04). There were no reductions in the need for transfusion.

Note. TXA = tranexamic acid; RCT = randomized clinical trial; IV = intravenous; pRBC = packed red blood cell; HR = hazard ratio; CI = confidence interval.

Efficacy in military settings

In a retrospective review of nearly 900 severely injured trauma patients presenting to a military combat hospital, the Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) study reported a 6.5% absolute survival benefit (27% relative risk reduction in mortality) with intravenous TXA given within 1 hour after injury (17.4% vs 23.9%, respectively; P = .03). ²⁶ The survival benefit was most pronounced among patients requiring massive transfusion. In a subsequent continuation of the MATTERs study, the authors reported an additive survival benefit with coadministration of TXA and cryoprecipitate. ²⁷ The authors postulated that the provision of fibrin substrate (cryoprecipitate) along with the hemostatic and anti-inflammatory effects of TXA accounted for the survival benefits.

A retrospective multicenter study by Howard et al ²⁸ failed to show a similar mortality reduction with TXA in 3773 severely injured trauma patients treated at a military combat hospital. The authors noted a nonsignificant trend toward increased survival benefit with TXA and suggested that larger enrollment was needed to show significance. Eckert et al ²⁹ evaluated the use of TXA in pediatric trauma in a retrospective review of nearly 800 patients age 18 or younger presenting to a military combat hospital. The study demonstrated a modest survival benefit with TXA (odds ratio [OR], 0.27; 95% confidence interval [CI], 0.85-0.89; P = .03) among severely injured children when compared against propensity-matched controls. The authors further noted a statistically significant increase in Glasgow Coma Scale (GCS) scores at discharge among children who received TXA (mean GCS of 8 in TXA vs 13 in non-TXA group; P < .001) when compared with propensity-matched controls with similar GCS scores on arrival.

Intracranial Hemorrhage

Traumatic brain injury

Hemorrhagic brain injury contributes significant morbidity and mortality to patients following traumatic injury. Perel et al evaluated the effects of intravenous TXA (loading dose of 1 g over 10 minutes followed by 1 g over 8 hours vs matching placebo) following hemorrhagic TBI in a nested study of more than 200 patients enrolled in the CRASH-2 study. Treatment with TXA was associated with a 7% reduction in all-cause mortality, a 5.6% reduction in head injury–related mortality, and a 13.3% reduction in overall poor outcomes. The trial team reported a high probability of decreased hemorrhage growth, intracranial mass effect, and new hemorrhage development, when compared with matched controls. ³⁰ This study reported a benefit with TXA for all intracranial hemorrhage subtypes except epidural hematomas. The authors reported no new intracranial ischemic infarcts in patients receiving TXA when compared with placebo.

The results of the CRASH study series were expanded after the publication of the CRASH-3 trial in 2019. ³¹ The trial collaborators performed a randomized, placebo-controlled trial measuring the effect of TXA administration within 3 hours of injury (loading dose of 1 g over 10 minutes followed by 1 g over 8 hours vs matching placebo) on head injury–related deaths for adults with TBI. The trial was performed over the span of 7 years throughout 175 hospitals in 29 countries, and found that early treatment was more effective than late treatment for mild to moderate head injury (P = .005) and the risk of head injury–related death was reduced with TXA. ³¹ There was no effect on mortality among patients who suffered from severe head injury. The risk of seizure and vascular occlusive events was similar in the treatment and placebo groups. This therapeutic benefit, while less robust than those reported in the CRASH-2 trial, still suggests a similar rate of reduced blood loss after mild to moderate head injury. ³¹

Atraumatic intracerebral hemorrhage

Acute intracerebral hemorrhage is the second most common cause of stroke. ³² Subsequent hemorrhage expansion, identified in roughly 25% of nontraumatic intracerebral hemorrhages, correlates with poor functional outcomes. ³³ In a multicenter randomized control trial evaluating 2325 non-anticoagulated patients presenting within 8 hours of symptom onset following atraumatic intracerebral hemorrhage, intravenous TXA appeared to offer no benefit over placebo regarding functional status at 90 days. ³³ Similarly, no mortality benefit was noted at 90 days. Although no functional or mortality benefits were seen, the study did report a significant decrease in both hematoma expansion and hematoma volume in patients receiving TXA. No difference in arterial or venous thrombotic events was seen in association with TXA.

Anterior Epistaxis

Epistaxis is a very common presentation in US EDs. As much as 60% of individuals will experience one or more episodes of epistaxis in their lifetime, with risk increasing with age. Among those who experience epistaxis, 6% will seek emergency medical treatment.^34,35 Multiple treatment options exist for epistaxis, including nasal packing, ³⁶ hemostatic gel matrices, ³⁷ and chemical cauterization. ³⁸ Antiplatelet and anticoagulant use, both increasingly common among older patients, are associated with greater severity and recurrence of epistaxis, and greater likelihood of receiving invasive interventions within EDs and otolaryngologic clinics. ³⁹ Patients who have experienced epistaxis are more likely to discontinue prescribed antiplatelet and anticoagulant therapy, which may increase their risk related to conditions managed with these medications. ⁴⁰ The potential morbidity associated with refractory epistaxis, with its treatment, and with potential subsequent discontinuation of prescribed antiplatelet and anticoagulation therapies could be reduced by effective alternative treatments for epistaxis.

Topical TXA use in anterior epistaxis, applied via nasal pledget saturated in TXA 500 mg/5 mL intravenous solutions, has been assessed in multiple RCTs comparing topical TXA to standard care with epinephrine and nasal packing. Zahed et al in an RCT reported among 216 patients with epistaxis a faster resolution of bleeding, a lower recurrence rate, and greater patient satisfaction with TXA administered topically. They found that 95% of patients receiving TXA were discharged within 2 hours from arrival to the ED, compared with 6.4% (14.8 [95% CI, 7.2-30.4], P < .001) for patients receiving standard therapy. ⁴¹ In a subsequent study of TXA among patients receiving antiplatelet therapy, Zahed et al in another RCT found among 164 patients that topically administered TXA was associated with faster resolution of bleeding, lower bleeding recurrence rates, greater patient satisfaction, and faster discharge from the ED. ⁴² Morgenstern et al ⁴³ showed similar improvements with topical TXA (500 mg of TXA soaked on cotton pledget) over nasal packing in time to epistaxis resolution (risk ratio [RR], 44%; P = .001), bleeding recurrence rates, ED length of stay, and patient satisfaction in a prospective RCT of 124 patients taking antiplatelet agents. A recent Cochrane Systematic Review of 6 randomized controlled trials (including the 2 studies by Zahed et al, discussed above) of TXA in epistaxis found moderate-quality evidence of a benefit with TXA in both the risk of bleeding recurrence and the time to bleeding resolution. ⁴⁴ Birmingham et al subsequently evaluated topical TXA in epistaxis nonresponsive to firstline topical agents in a retrospective review study of 122 ED patients. They found no reduction in length of stay among patients who received TXA but did identify a decrease in both nasal packing and otolaryngologic consultation following TXA. ⁴⁵ A current, ongoing multicenter RCT enrolling 450 patients aims to further assess the effects of TXA on the rate of nasal packing for refractory epistaxis ⁴⁶ (Table 2).

Table 2.

Effect of TXA Compared With Standard of Care on Outcomes in Anterior Epistaxis.

Authors	Duration of epistaxis	ED/hospital length of stay	Recurrence of epistaxis	Patient satisfaction	Frequency of otolaryngologist consultation
Zahed et al 41	39.8% increase in hemostasis achieved within 10 minutes for TXA (P < .001)*	88.9% increase in ED discharge in <2 hours for the TXA group (P < .001)*	6.3% reduction in recurrence for TXA after 24 hours (P = .128)	Patient satisfaction for TXA: (8.5 ± 1.7) compared with (4.4 ± 1.8) (P < .001)*	NA
Zahed et al 42	44% increase in hemostasis achieved within 10 minutes for TXA (P < .001)*	76% increase in ED discharge in <2 hours for the TXA group (P < .001)*	5% reduction in recurrence for TXA after 24 hours, 16% reduction after 1 week (P = .007)*	Median patient satisfaction of 9 for TXA vs 4 for standard (P < .001)*	NA
Morgensternet al 43	44% increase in hemostasis achieved within 10 minutes for TXA (P < .001)*	76% increase in ED discharge in <2 hours for the TXA group (P < .001)	16% reduction for the TXA group (P = .007)	Generally reported higher patient satisfaction for TXA	NA
Joseph et al 44	NA	1.6-day decrease in hospital LOS for TXA in 1 study and no evidence of difference in other study	20% decrease for oral TXA and 23% decrease for topical TXA	NA	NA
Birminghamet al 45	NA	272-minute ED LOS for TXA vs 232 minutes for standard (P = .26)	NA	NA	30% decrease for TXA (P = .002)*

Note. ED = emergency department; NA = variable not measured by the study; TXA = tranexamic acid; LOS = length of stay.

^*P values that are statistically significant.

Hematuria

Gross hematuria is commonly encountered in the ED and may be associated with underlying infection, calculus, tumor, trauma, or vascular abnormality of the genitourinary tract. ⁴⁷ Management of gross hematuria is multifactorial, often including volume resuscitation, blood product replacement, and surgical intervention. Tranexamic acid use in the management of gross hematuria has been described in case reports and case series of patients with autosomal dominant polycystic kidney disease.^48,49 More recently, Moharamzadeh et al reported faster resolution of hematuria with intravesicular TXA irrigation (500 mg/100 mL via a 3-branch catheter) in a small randomized controlled trial of 50 patients with gross hematuria. The authors found reduced bladder irrigate requirements (9.52 ± 4.13 L in the tranexamic group vs 12.00 ± 4.22 L in the placebo group; P = .04) and a faster time to resolution of microscopic hematuria in the TXA group (P = .026). ⁵⁰

Postpartum Hemorrhage

Postpartum hemorrhage is the leading cause of maternal death worldwide and accounts for more than 100 000 maternal deaths each year. ⁵¹ Emergent treatments for postpartum hemorrhage are complex and may involve uterotonic agents, hemostatic agents, and surgical interventions, including emergent hysterectomy. The prevalence of emergency postpartum hysterectomy is 0.61 per 1000 deliveries in high-income countries and carries a 3% mortality rate; the prevalence in low-income countries is estimated at 2.8 per 1000 deliveries, with mortality rates of 12%.^52,53

In a small RCT of 144 patients conducted in France, Ducloy-Bouthors et al found that intravenous TXA decreased the need for blood product transfusion and the transfusion volume required in postpartum hemorrhage. The authors also reported a nonsignificant trend toward reduced need for invasive interventions in patients receiving TXA. ⁵⁴ A subsequent large multinational randomized controlled trial by the World Maternal Antifibrinolytic Trial (WOMAN Trial) Collaborators investigated the use of intravenous TXA in more than 20 000 patients experiencing postpartum hemorrhage. The authors reported a modest, but significant, decrease in death from bleeding in patients receiving TXA (1.5% vs 1.9%). The authors further reported a significant decrease in the rate of emergent laparotomy in patients receiving TXA. The authors did not, however, find a significant difference in all-cause mortality or in the rate of emergent postpartum hysterectomy among groups. ⁵⁵ Following the publication of the findings on TXA by the WOMAN Trial Collaborators, the World Health Organization (WHO) published an update on the management of postpartum hemorrhage, strongly recommending the use of intravenous TXA within 3 hours of childbirth in the presence of hemorrhage ⁵⁶ (Table 3).

Table 3.

Selected Studies Analyzing the Effect of TXA on Postpartum Hemorrhage Outcomes.

Authors	Design	No. of patients	Methods	Conclusions
Ducloy-Bouthors et al 54	Open-label RCT	144	Women with postpartum hemorrhage of >800 mL were randomized to receive 4 g TXA over 1 hour, then 1 g/h for 6 hours, or standard care.	Blood loss within the first 6 hours of enrollment was significantly lower in the TXA group (173 mL median) compared with the control group (221 mL median) (P = .041). Tranexamic acid was associated with a decreased need for blood transfusion and total volume transfused.
WOMAN Trial Collaborators 55	Double-blinded RCT	20 060	Women with postpartum hemorrhage were randomly assigned to receive 1-g intravenous TXA or placebo. Women with subsequent hemorrhage recurrence within 24 hours were provided with additional 1 g TXA or placebo.	Rates of bleeding deaths were significantly lower in the TXA group (1.5%) compared with the placebo group (1.9%) (P = .045). Although TXA did not significantly decrease all-cause mortality, it did modestly decrease death from bleeding. Effects were most notable in patients receiving TXA within 3 hours.

Note. TXA = tranexamic acid; RCT = randomized clinical trial; WOMAN Trial = World Maternal Antifibrinolytic Trial.

GI Bleeding

Acute GI hemorrhage represents a common and severe presentation in the ED and carries a mortality risk of 3% to 10%. Severe GI hemorrhage presents with hematochezia, and the most commonly identified underlying lesions include diverticula and vascular ectasias.^57,58 To date, few studies have evaluated TXA use (administered by both oral and intravenous routes) in acute GI hemorrhage. A 2014 meta-analysis included 8 RCTs (1701 patients) that evaluated the utility of TXA in treating upper GI hemorrhage. ⁵⁹ The study concluded that TXA might have a beneficial effect on mortality, though cautioned against generalization of the findings of the included studies. A subsequent retrospective cohort study evaluated the protocolized use of TXA in severe GI hemorrhage in 36 patients. The authors reported decreased utilization of blood product transfusion following TXA administration, though they also acknowledged several limitations precluding generalization of these results, namely, being a single-center study and retrospective design. ⁶⁰ More recently, Smith et al conducted a small randomized controlled trial of TXA use in 100 patients with lower GI hemorrhage and reported no significant effects on hemoglobin concentrations, transfusion rates, or mortality with TXA. The authors acknowledged that the study may have been underpowered to identify smaller clinical effects of TXA. ⁶¹ The Halt-It study is an ongoing, international, randomized controlled trial of TXA begun in 2013 and aiming to enroll 12 000 patients with acute GI hemorrhage by 2019. ⁶² The EXARHOSE study is an ongoing randomized interventional trial that is measuring the efficacy of TXA administration on acute upper GI bleeding in cirrhotic patients that aims to enroll 500 patients by 2019. ⁶³

Discussion

In this review, we discuss the evidence on the use of TXA in multiple clinical environments and for varied clinical conditions. Although the literature supporting the use of TXA is most robust in the settings of trauma and postpartum hemorrhage (Tables 1 and 3), we present further evidence for its use in nontraumatic hemorrhagic strokes, acute epistaxis (Table 2), severe hematuria, and GI hemorrhage. There is a growing body of literature on TXA and its effects following both systemic and topical administration.^64-67

Large trials evaluating TXA are ongoing, and identification of patients most likely to benefit from TXA remains elusive. The current evidence suggests that TXA is a useful adjunct in severe hemorrhage, irrespective of the underlying cause (Table 4).

Table 4.

TXA Administration Protocols Described in Reviewed Studies.

Clinical setting	Level of evidence	Treatment
Anterior epistaxis	RCT	TXA 500 mg injectable form applied topically with saturated cotton pledget to the affected nostril until bleeding ceases41,42
Hematuria	Case report, case series, small RCT	TXA 500 mg injectable form dissolved in 100 mL normal saline washed into the bladder via a 3-branch catheter 50
Gastrointestinal hemorrhage	Meta-analysis, retrospective cohort	Both intravenous and oral therapies were attempted, with dosages ranging from 4 to 8 g and length of therapy ranging from 2 to 7 days 59
Postpartum hemorrhage a	RCT	TXA 1 g intravenous injection followed by additional 1 g if bleeding continues or if bleeding recurs within 24 hours 55
Traumatic hemorrhage b	RCT	TXA 1 g intravenous injection over 10 minutes followed by additional 1 g over 8 hours, initiated within 8 hours of hemorrhage onset; cryoprecipitate, 1 unit, may be coadministered with a potential additive beneficial effect19,22
Hemorrhagic traumatic brain injury	RCT	TXA 1 g intravenous injection over 10 minutes followed by additional 1 g over 8 hours, initiated within 8 hours of hemorrhage onset30,31
Atraumatic intracranial hemorrhage	RCT	TXA 1 g intravenous injection over 10 minutes followed by additional 1 g over 8 hours, initiated within 8 hours of hemorrhage onset b 33

Note. RCT = randomized clinical trial; TXA = tranexamic acid.

^aLarger, randomized controlled studies given preference for the purposes of this table when different study authors used differing dosage protocols.

^bTXA was associated with reduced hematoma expansion and hematoma volume, but did not have appreciable effects on mortality or functional status at 90 days.

Prior studies have documented a theoretical risk of vascular thrombosis following treatment with antifibrinolytic drugs, including TXA, and 1 large study reported an increase in thrombotic events with TXA.^20,28,68 Multiple studies, including 2 multinational randomized control trials enrolling more than 40 000 combined patients, failed to identify an increased risk of thrombosis following TXA administration.^19,55 A subsequent meta-analysis further suggested no increase in vascular thrombosis with TXA. ¹⁵ Still, there may exist a subset of patients at increased risk of thrombotic events following TXA administration, such as patients with known congenital or acquired hypercoagulable states. Most studies included in this review excluded patients with known or perceived increased risk for thrombosis.

Prior case reports and case series have linked TXA use with an increased seizure risk. ⁶⁹ Most reports describe seizures following TXA use in cardiac surgery, and many report seizures following TXA administered in doses significantly higher (80-100 mg/kg cumulative dose) than those reported in the studies described in this review. Still, some studies reviewed here reported seizure history among exclusion criteria for TXA administration. Given the available evidence, consideration of seizure risk appears warranted prior to administration of TXA in acute hemorrhage.

Limitations

This review has several limitations. Some studies included in this review were conducted in inpatient cohorts, whereas others were conducted in the outpatient setting, thus limiting the applicability to an ED setting. Many of the included trials enrolled small numbers of participants, limiting the statistical power of any reported outcomes with TXA. Case reports and case series were included in this review only where little or no other research exists. Nonetheless, great caution must be exercised in drawing conclusions from such reports. Additional limitations include the exclusion of non–English-language publications, and study designs excluding enrollment of patients with perceived increased risk for thrombotic events. Although most available data suggest no increased thrombotic risk exists, care must be taken when considering the use of TXA in these at-risk patients. Aminocaproic acid is also a synthetic antifibrinolytic that is mostly used in postsurgical bleeding in the operating room and is not included in this review as we chose to limit our literature search to data regarding TXA.

Conclusions

Acute hemorrhage is a leading cause of death both in the United States and globally. Treatment of acute hemorrhage is complex, involving both medical management and procedural intervention. Tranexamic acid is an increasingly studied adjunct in the management of acute hemorrhage and appears to offer a modest survival benefit in severely ill and injured patients with acute blood loss. Adverse events, most notably venous thrombus formation and acute seizures, occur rarely and may be associated only with very large dosing regimens (80-100 mg/kg cumulative dose). Although further evidence is needed to better identify patients most likely to benefit from TXA, there is supporting evidence that its use in acute, severe hemorrhage may serve as a valuable adjunct to the acute care clinician.